injuries to the peripheral nervous system can result in physical discontinuity of a peripheral nerve, leaving two uncoupled nerve ends, if the gap between these ends is relatively small (<20 mm), the nerve ends are surgically sutured together after which normal regenerative processes lead to eventual recovery in most cases. For larger gaps, the most successful solution currently available is the use of a sensory nerve autograft. Alongside the fact that even autografts are successful only 50% of the time, problems such as donor-site morbidity and donor nerve shortage prompt the search for alternative methods for promoting peripheral nerve regeneration.
A promising method known as nerve entubulation involves the use of hollow cylindrical chamber called nerve guide or nerve guidance channel (NGC), in which both ends of the nerve are placed. Such a nerve guide is designed to facilitate regenerating axons at the proximal nerve end to grow towards the distal end while preventing fibrous tissue infiltration or neuroma formation. It also leads to the accumulation of trophic (growth/survival promoting) and tropic (growth direction controlling) factors secreted by the distal nerve end within the guide, further encouraging effective nerve regeneration. In addition, nerve guide walls serves to mechanically ensure nerve end regeneration in the right direction.
The most important component of nerve guides is their ability to furnish a biochemical environment conducive to nerve re-growth. Such a biochemical microenvironment should include adhesion guidance signal, e.g. cell adhesion molecules and neurotrophic and tropic cues secreted by the Schwann cells. Cell adhesion cues facilitate binding and support the growth of Schwann cells and axons and thereby accelerate axonal regeneration. The latter can be provided by including or recruiting Schwann cells, or by incorporating these bioactive factors in the guides.
Incorporation of neurotrophic factors in nerve guides is a more controlled, effective, and yet complex approach. Growth factors such as NGF, BDNF, CNTF, GDNF, and FGF have been shown to elicit various different neural responses, and when combined in the right spatiotemporal profiles, they can encourage axon survival and outgrowth. The most primitive means of including growth factors into nerve guides is by filling the channel with a growth factor solution. Problems with this approach include leakage of growth factors from the nerve guide and growth factor inactivation. While continuous delivery devices such as osmotic pumps and silicone reservoirs have been used to overcome these problems, they also suffer from complications such as device failure and inflammation resulting from the non-degradable components. These considerations have propelled research focusing on delivery of growth factors using degradable polymer matrices or microcapsules. Current technologies focus on incorporating the growth factor directly into the nerve guide wall and attempting to choose a wall material that will controllably release the growth factor. Additional methods include the incorporation of growth factor in microcapsules for further tuning their release, and cross-linking growth factors directly to the scaffold material. Complications with these methods arise also, however, due to the fact that growth factor release cannot be controlled tightly; some growth factors may be toxic when delivered at a high local concentration. Even further, a problem known as the “growth-factor oasis” effect has been observed in which high levels of growth factors within the nerve guide allow axons to regenerate into the nerve guide but not out, because the regenerating axons simply become fixed to the local maximum in the growth factor concentration profile. Therefore controlling growth factor concentration and release profile in nerve guides is critical to the effectiveness of this approach.
The palette of growth factors that promote neural regeneration is well-characterized; however, what is less understood is the post-injury time frame where they have the optimal effect and the specificity of various neurotrophic factors. The poor control of neurotrophic factor encapsulation and release has been the limiting factors to develop an efficient release system to fully harness the potential benefits of local sustained release of neurotrophic factors to improve PNS regeneration.
Aligned nanofiber lining the nerve guide lumen has been shown to improve the axonal re-growth, likely though promoting the adhesion and growth of Schwann cells and/or offering guidance for axonal re-growth. In the previous nanofiber nerve guide configurations, nanofibers serve both as a guidance cue and a delivery carrier for neurotrophic factors. The complication is that a) loading neurotrophic factors with controlled dose and release kinetics has been difficult; b) growth factor loading involves organic solvent and harsh conditions, which will significantly decrease the bioactivities of the growth factors; c) it is difficult to adjust the total dose of growth factors and the nanofibers independently.
Accordingly, the need exists for more effective nerve guides for use in regeneration of for example, peripheral nerves.